Calreticulin exposure is a novel prognostic marker for AML patients

Immunogenic Cell Death (ICD) is a mechanism whereby neoplastic cells yielding to specific treatment can activate the immune system by releasing danger signals called Damage Associated Molecular Patterns (DAMPs). ICD-relevant DAMPs include the exposure of endoplasmic reticulum chaperones such as Calreticulin (CRT). DAMPs such as CRT, mediate robust immunostimulatory effects upon interaction with pattern recognition receptors. Little is known about the prognostic relevance of CRT in Acute Myeloid Leukemia (AML) patients that receive ICD inducers such as anthracyclines and bortezomib.  

Dr Jitka Fucíková from Charles University, Prague, Czech Republic, and colleagues recently published their findings, which was based on the immunological and prognostic relevance of CRT exposure in AML patients. The data was first published ahead of print on 1 November 2016 in Blood.  

Highlights:

• Fifty AML patients were analyzed in this study
• Prior to treatment, 82% of AML patients had >5% CD45+CD33+ blasts with Surface-Exposed CRT (ecto-CRT) compared to <5% in control; P = 0.0017
• Premortem ER stress protein mRNA levels including ATF4, DDIT3, and HSPA5 had a significant correlation with ecto-CRT+ blasts
• CRThi and CRTlo AML patients had significant upregulation of TH1 polarization (P < 0.05), CD8+ T-cell cytotoxicity (P < 0.05) and T-cell activation (P < 0.05) after complete remission and recovery
• Significant overexpression of Natural Killer (NK) cell-related genes in CRThi compared to CRTlo
• Leukemia-Associated Antigens (LAAs)-specific CD4+ and CD8+ T-lymphocytes were found in higher levels in the peripheral blood in CRThi compared to CRTlo AML patients
• Median Relapse Free Survival (RFS) between CRThi & CRTlo; 692 vs 141 days, P = 0.002
• Median Overall Survival (OS) between CRThi & CRTlo; 665 vs 252 days, P = 0.033

CRT exposure reflects a clinically relevant, AML-specific immune response and monitoring CRT exposure on malignant blasts could identify a subset of patients with AML that respond to some forms of immunotherapy. The authors concluded by stating that overexpression and exposure of CRT represents a novel powerful prognostic biomarker for AML patients treated with chemotherapy.

Abstract

Cancer cell death can be perceived as immunogenic by the host only when malignant cells emit immunostimulatory signals (so-called "damage-associated molecular patterns," DAMPs), as they die in the context of failing adaptive responses to stress. Accumulating preclinical and clinical evidence indicates that the capacity of immunogenic cell death to (re-)activate an anticancer immune response is key to the success of various chemo- and radiotherapeutic regimens. Malignant blasts from patients with acute myeloid leukemia (AML) exposed multiple DAMPs, including calreticulin (CRT), heat-shock protein 70 (HSP70), and HSP90 on their plasma membrane irrespective of treatment. In these patients, high levels of surface-exposed CRT correlated with an increased proportion of natural killer cells and effector memory CD4+ and CD8+ T cells in the periphery. Moreover, CRT exposure on the plasma membrane of malignant blasts positively correlated with the frequency of circulating T cells specific for leukemia-associated antigens, indicating that ecto-CRT favors the initiation of anticancer immunity in patients with AML. Finally, although the levels of ecto-HSP70, ecto-HSP90, and ecto-CRT were all associated with improved relapse-free survival, only CRT exposure significantly correlated with superior overall survival. Thus, CRT exposure represents a novel powerful prognostic biomarker for patients with AML, reflecting the activation of a clinically relevant AML-specific immune response.